RNA quality control and environmental stress

RNA质量控制和环境压力

• 批准号: 7431614
• 负责人: Sandra L. Wolin
• 金额: $ 39.92万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7431614
• 关键词: Animals; Autoimmune Diseases; Bacteria; Binding; Biological Process; Cell Line; Cell Nucleus; Cell Survival; Cell physiology; Cells; Complex; Cytoplasm; Disease; Eubacterium; Exonuclease; Exoribonucleases; Failure; Goals; Immune response; Mammalian Cell; Mus; Nuclear; Pathway interactions; Patients; Play; Polyribonucleotide Nucleotidyltransferase; Process; Protein Binding; Proteins; Quality Control; RNA; RNA Degradation; RNA Helicase; RNA-Binding Proteins; Ribonucleases; Role; SS-A antigen; Scaffolding Protein; Small RNA; Stress; Systemic Lupus Erythematosus; Testing; Xenopus oocyte; disulfide bond; insight; irradiation; novel; protein misfolding; repaired; ultraviolet irradiation

DESCRIPTION (provided by applicant): The long term goals of this project are to understand how misfolded RNAs are recognized and handled within cells and to investigate how RNA misfolding impacts cell function. Our focus is on the Ro autoantigen, an RNA-binding protein that is a major target of the immune response in patients with systemic lupus erythematosus. In the cytoplasm of many animal cells, Ro binds small RNAs called Y RNAs. Although the function of the Ro/Y RNA complex has been enigmatic, we recently demonstrated that Ro has 2 conserved cellular functions. First, Ro binds misfolded, defective small RNAs in vertebrate cell nuclei, and thus likely plays a role in small RNA quality control. Second, Ro is part of a novel pathway by which mammalian cells and at least one eubacterium survive ultraviolet irradiation. Consistent with a role in the recognition or repair of nuclear damage, Ro accumulates in nuclei following irradiation. Most surprisingly, mice lacking Ro develop an autoimmune disease that resembles systemic lupus erythematosus in patients. These findings suggest that this putative RNA quality control pathway may be important for protecting cells from environmental stress and raise the possibility that failure of RNA quality control may result in disease. Our goal is to arrive at a mechanistic understanding of Ro function and to uncover the role that Y RNAs play in these processes. Our first aim is to determine how Ro recognizes misfolded RNAs and to investigate whether binding by Ro targets them for degradation. Our second aim is to elucidate the mechanism by which Ro facilitates mammalian and bacterial cell survival following ultraviolet irradiation. Our third aim is to examine the role of the Y RNAs in small RNA quality control and cell survival after irradiation. As Ro is the only protein described to bind misfolded small RNAs in cells, a study of its function should provide insights into a little-studied but highly important biological process.

描述（由申请人提供）：该项目的长期目标是了解如何在细胞中识别和处理错误折叠的RNA，并研究RNA错误折叠如何影响细胞功能。我们的重点是RO Autoantigen，这是一种RNA结合蛋白，是全身性红斑狼疮患者免疫反应的主要靶标。在许多动物细胞的细胞质中，RO结合了称为Y RNA的小RNA。尽管RO/Y RNA复合物的功能是神秘的，但我们最近证明RO具有2个保守的细胞功能。首先，RO在脊椎动物细胞核中结合错误折叠的小RNA缺陷，因此很可能在小的RNA质量控制中起作用。其次，RO是一种新的途径的一部分，哺乳动物细胞和至少一个卵细菌在紫外线照射下生存。与识别或修复核损伤的作用一致，RO在照射后积累了核。最令人惊讶的是，缺乏RO的小鼠会形成一种自身免疫性疾病，类似于患者的全身性红斑狼疮。这些发现表明，这种假定的RNA质量控制途径对于保护细胞免受环境压力可能很重要，并增加了RNA质量控制失败可能导致疾病的可能性。我们的目标是对RO功能有一种机械理解，并揭示Y RNA在这些过程中所扮演的角色。我们的第一个目的是确定RO如何识别错误折叠的RNA，并调查RO的结合是否靶向降解。我们的第二个目的是阐明紫外线照射后RO促进哺乳动物和细菌细胞存活的机制。我们的第三个目的是检查Y RNA在照射后的小RNA质量控制和细胞存活中的作用。由于RO是唯一结合细胞中错误折叠的小RNA的蛋白质，因此对其功能的研究应提供深入的见解，以了解一些研究略有研究但非常重要的生物学过程。